AN APPLICATION TO RECOMMEND THAT FIXED DOSE COMBINATION THERAPY BE ADDED TO THE WHO MODEL LIST OF ESSENTIAL MEDICINES FOR SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE (ISCHEMIC HEART DISEASE AND THROMBOTIC ) (12)

Mark D. Huffman, MD, MPH, Northwestern University Feinberg School of Medicine, Chicago, USA

Shanthi Mendis, MBBS, MD, FRCP, World Health Organization, Geneva, Switzerland

Valentin Fuster, MD, PhD, Mount Sinai School of Medicine, New York, USA

Anthony Rodgers, MD, The George Institute, Sydney, Australia

Sidney C. Smith, Jr MD, University of North Carolina, Chapel Hill, NC, USA

Salim Yusuf, MD, DPhil, MRCP, Population Health Research Institute, McMaster University, Hamilton, Canada

1 1. Executive Summary

The World Health Organization (WHO) has recently announced its “25 by 25” target of reducing the burden of premature (<70 years) mortality from non-communicable, chronic diseases (NCDs) by 25% by the year 2025. Cardiovascular diseases (CVD), including ischemic heart disease and stroke, are the leading causes of death worldwide, yet less than half of all patients with prior disease take any medication for CVD secondary prevention and control. Fixed dose combination therapy including , beta-blockers, ACE-inhibitors, and statins have been advocated by the WHO for CVD secondary prevention since 2001 given the benefits in terms of efficacy, adherence, scalability, and cost-effectiveness. Several versions of fixed dose combination therapy for CVD secondary prevention have been developed and studied within the past few years. Recent clinical trials have demonstrated similar bioequivalence with similar (or greater) reductions in risk factors as well as a 33% increase in adherence compared with usual care in CVD secondary prevention. Given the urgent need for improved CVD prevention and control, we propose the inclusion of fixed dose combination therapies outlined below for CVD secondary prevention in the WHO Model List of Essential Medicines.

2. Name of the focal point in WHO submitting or supporting the application

Dr. Shanthi Mendis, Coordinator, Chronic Disease Prevention and Management.

3. Name of the organizations consulted and/or supporting the application

Individuals on behalf of organizations supporting the application are listed below (in alphabetical order):

Name Institute Country

Attaran, Amir University of Ottawa Canada

Avezum, Alvaro Dante Pazzanese Institute of Cardiology Brazil

Baigent, Colin Clinical Trials Service Unit United Kingdom

Beaglehole, Robert University of Auckland New Zealand

Bots, Michiel University Medical Center Utrecht Netherlands

Bovet, Pascal Institut Universitaire de Médecine Sociale et Preventive Switzerland

Bullen, Chris University of Auckland New Zealand

Chow, Clara The George Institute for Global Health Australia

Dans, Antonio University of the Philippines Philippines

Diaz, Rafael Estudios Cardiologicos Latino America Argentina

2 Elley, Raina University of Auckland New Zealand

Enas, Enas CADI Research Foundation United States

Gaziano, Tom Harvard School of Public Health United States

Gerstein, Hertzel McMaster University Canada

Grassi, Guido Università degli Studi Milano-Bicocca Italy

Grobbee, Diederick University Medical Center Utrecht Netherlands

Hart, Robert McMaster University Canada

Keltai, Matyas Hungarian Institute of Cardiology Hungary

Kengne, Andre South African Medical Research Council South Africa

Lafeber, Melvin University Medical Center Utrecht Netherlands

Liu, Lisheng National Center of Cardiovascular Diseases China

Lonn, Eva McMaster University Canada

Lopez-Jaramillo, Patricio Fundacion Oftalmológica de Santander Colombia

Mayosi, Bongani Pan African Society of Cardiology South Africa

McKee, Martin London School of Hygiene and Tropical Medicine United Kingdom

Mills, Ed University of Ottawa Canada

Narayan, Venkat Emory University United States

Neaton, Jim University of Minnesota United States

Niessen, Louis Johns Hopkins University United States

Paccaud, Fred Institut Universitaire de Médecine Sociale et Preventive Switzerland

Pais, Prem St John’s National Academy of Health Sciences India

Prabhakaran, D Centre for Chronic Disease Control India

Reddy, K. Srinath Public Health Foundation of India India

Sadanandan, Rajeev Government of Kerala India

Sanz, Gines Centro Nacional de Investigaciones Cardiovasculares Spain

Schwalm, JD McMaster University Canada

Selak, Vanessa University of Auckland New Zealand

Smith, Richard UnitedHealth Chronic Disease Initiative United Kingdom

3 Smith, Sidney World Heart Federation Switzerland

Szuba, Andrzej Wroclaw Medical University Poland

Teo, Koon McMaster University Canada

Varigos, John Monash University Australia

Vijay, Kris Cardio Renal Society of America United States

Webster, Ruth The George Institute for Global Health Australia

Weissberg, Jed Kaiser Permanente United States

Wood, Bobbe Heart & Stroke Foundation of Canada Canada

Xavier, Denis St John’s National Academy of Health Sciences India

Yeates, Karen Queen’s University Canada

Yusoff, Khalid Universiti Teknologi MARA Malaysia Maria Skłodowska-Curie Memorial Cancer Center and Zatonski, Witold Poland Institute of Oncology Zhu, Jun Chinese Academy of Medical Sciences China

4. International Proprietary Name (INN) a) Indian Polycap (aspirin, simvastatin, , , ) b) Sincronium (México)/Trinomia (rest of the world) (aspirin, simvastatin, ramipril) c) Red Heart Pill 1 (aspirin, simvastatin, lisinopril, atenolol) and Red Heart Pill 2 (aspirin, simvastatin, lisinopril, hydrochlorothiazide)

5. Formulation proposed for inclusion a) Indian Polycap (low dose: aspirin 100 mg, simvastatin 20 mg, ramipril 5 mg, atenolol 50 mg, hydrochlorothiazide 12.5 mg; high-dose: aspirin 200 mg, simvastatin 40 mg, ramipril 10 mg, atenolol 100 mg, and hydrochlorothiazide 25 mg) b) Trinomia/Sincronium (aspirin 100 mg, simvastatin 40 mg, and ramipril (2.5 mg, 5 mg, or 10 mg)) c) Red Heart Pill 1 (aspirin 75mg, simvastatin (20 or 40mg), lisinopril 10mg, atenolol 50mg) and Red Heart Pill 2 (aspirin 75mg, simvastatin (20 or 40mg), lisinopril 10 mg, hydrochlorothiazide 12.5 mg)

6. International availability The Indian Polycap (Cadila) is currently available in India.

4 Trinomia/Sincronium (Ferrer) is available in Guatemala and México and will soon be available in Argentina and Nicaragua.

Regulatory submissions for the Red Heart Pills 1 and 2 (Dr. Reddy’s Laboratories, Ltd.) have been developed and are planned for submission by early 2013.

As of November 2012, the Indian Polycap and Trinomia/Sincronium pill are manufactured by companies in two countries (Table 1). The George Institute for Global Health is now negotiating a global license for the Red Heart Pill products following a recent decision by the current manufacturer (Dr. Reddy’s Laboratories, Ltd.) not to proceed with taking the products to market because of existing regulatory requirements. The George Institute has nearly completed its licensing agreement with Dr. Reddy’s Laboratories, Ltd. for production through an alternate manufacturer.

Table 1. List of countries in which indicated drugs are manufactured and/or formulated. Company Manufacturing Company Manufacturing Country Indian Polycap Trinomia/Sincronium India Cadila Pharmaceuticals, Ltd. Spain Ferrer International

7. Listing as individual medicine or representative of therapeutic group Fixed dose combinations as listed above with the goal of future fixed dose combinations to be added to the Model List of Essential Medicines to update the Model List. Alternatively, fixed dose combination therapy could be considered under the “square box” category to indicate similar clinical efficacy.

8. Information Supporting the Public Health Relevance The World Health Organization (WHO) has recently announced targets for reducing the number of premature deaths (<70 years) due to non-communicable, chronic diseases (NCDs) by 25% by the year 2025.(1) These targets have been preceded by other WHO goals of reducing the burden of not only premature death but also disability from NCDs,(2) which were formalized as a result of the resulting Political Declaration from the 2011 United Nations High Level Meeting on NCDs.(3) Since cardiovascular diseases (CVD) are the leading causes of mortality in the world and since more than 80% of CVD deaths occur in low- and middle-income countries (LMICs),(4) CVD treatment and control are crucial to reaching these WHO targets. If current trends continue, CVD morbidity and mortality are projected to increase substantially in the coming decades.(5) However, CVD secondary prevention with fixed dose combination therapy has been deemed a “best buy” by the WHO(6) and organizations such as the NCD Alliance(7) given its efficacy, adherence, scalability and cost-effectiveness.(8) More than half of patients with prior ischemic heart disease or stroke receive no secondary medications,(9) yet the WHO’s recent indicators to reach its “25 by 25” target include provision that 50% of eligible people receive drugs to prevent heart attacks and .

5 A large amount of evidence supports the use of pharmacological treatment for the secondary prevention of cardiovascular death in patients with prior CVD events. Drugs including antiplatelet agents,(10) beta-blockers,(11) lipid-lowering agents,(12) and angiotensin-converting-enzyme inhibitors(13) have all demonstrated improvements in mortality and morbidity individually and are recommended for secondary prevention of CVD by a diverse group of professional organizations.(14) However, substantial gaps in coverage of CVD secondary prevention are widespread globally.(9) Reasons for these substantial gaps include lack of availability (stock-outs), poor adherence, unaffordable cost, and inadequate prescription of medicines. Fixed dose combination therapy that combines CVD secondary preventive medicines appears to overcome many of these barriers. Further, fixed dose combination therapy has been shown to improve adherence by 33% compared with usual care in CVD secondary prevention, thus meeting the Model List’s recommendation that fixed dose combination therapies should have “a proven advantage in therapeutic effect, safety or compliance over single compounds administered separately.”(15)

Although fixed dose combination therapy per se has not been tested for efficacy in secondary prevention of CVD, each of the components have individually demonstrated reduction of mortality and morbidity when given against a background of all other proven drugs. Therefore, the benefits of the drugs are additive. However, these medicines individually and when used in combination have also been shown to be well- tolerated. Recent trials indicate that fixed dose combination therapy reduces lipids (through which statins are thought to exert their beneficial effects) and (a marker of the effects of ACE inhibitors, beta-blockers and ) to the same extent as giving each one of them separately (an additive effect on the surrogate markers of efficacy) and that they are well tolerated. Similar or improved efficacy, tolerance, and adherence have been demonstrated both in individuals with prior CVD (compared against the individual components given separately) and in individuals without prior CVD (compared against placebo). Further, the efficacy of fixed-dose combination therapy with other medicines has been demonstrated in populations of patients with other conditions such as AIDS, tuberculosis and ,(16) thereby supporting the generic concept that using drugs in combination has merit.

Each individual component of fixed dose combination therapy is proven to reduce death, , or stroke in those with ischemic heart disease or stroke. The existing data on fixed dose combination therapy shows the combinatorial formulation reduces risk factors to the extent expected if the individual components were given individually. Therefore, the current consensus is that the fixed dose combination therapy should be considered for use in CVD secondary prevention. This conclusion is based on the existing data and the high-risk profile for CVD events in this group. Different expert panels, including the WHO(17) and the Combination Pharmacotherapy and Public Health Research Working Group(18), have recognized the potential value of applying the fixed dose combination therapy concept for secondary prevention of CVD.

6 Further, there is precedent in the inclusion of fixed dose combination therapy in the WHO Model List. Section 6.5.3.1 of the 17th Model List of Essential Medicines includes fixed dose combination therapy for curative treatment of Plasmodium falciparum malaria. The section states, “The list currently recommends combinations according to treatment guidelines. The Committee recognizes that not all of these FDCs exist and encourages their development and rigorous testing.” A similar argument can be made for fixed dose combination therapy for CVD secondary prevention. Overall, fixed dose combination therapy has an immense potential public health benefit as a low cost and readily available form, combining several proven treatments, to reduce the burden of CVD.

9. Treatment Details Cardiovascular disease secondary prevention includes treatment with aspirin, statin, beta-blocker, and ACE-inhibitor following a myocardial infarction or thrombotic stroke. These medications are typically to be used lifelong. Numerous professional organizations including the American Heart Association, American College of Cardiology,(14) European Society of Cardiology,(19) and United Kingdom’s National Institute of Health and Clinical Excellence(13) recommend these drugs for CVD secondary prevention given their efficacy and favorable risk-benefit profile.

10. Summary of comparative effectiveness in a variety of clinical settings Bioequivalence Study of the Polycap has demonstrated no indication of pharmacokinetic drug-drug interactions for any of the ingredients, with their bioavailabilities being well preserved.(20) Other fixed dose combination therapies demonstrate similar degrees of bioequivalence with the individual components.

Impact of Risk Factors The Indian Polycap Study (TIPS-1, 2007-2008) trial was the first clinical exposition of the beneficial effect of the use of a fixed dose combination pill (Polycap) for CVD prevention against individual or grouped available drug therapies. The study was performed in patients (2,053) without prior CVD but with at least one abnormal cardiovascular risk factor.(21) Statistical comparisons were performed referent to groups administered singular or combinational drug therapy with no equivalent active agent. Statistically significant reductions in blood pressure, low-density lipoprotein (LDL) cholesterol, total cholesterol and heart rate were found among Polycap participants in comparison to applicable groups without the effective drug. The short-term trial did not assess mortality. Based on risk factor changes, the TIPS-1 trial found that administration of Polycap could potentially reduce CVD by 62% as a combined reduction of risk due to LDL cholesterol, diastolic blood pressure, and platelet function.

This trial was followed by TIPS-2 (2012) to evaluate the added effect of a potassium supplement on a once daily Polycap prescription.(22) The TIPS-2 study additionally sought to determine efficacy and tolerability of a full dose Polycap prescription versus the half dose used during the TIPS-1 study. Patients (518) with a history of vascular disease or mellitus were randomized to a treatment arm of Polycap or Polycap

7 Plus (full dose Polycap [two tablets] plus 30 mEq/L potassium supplement). Analysis was performed between groups to assess the added effect of potassium. The Polycap Plus demonstrated statistically significant reductions in total and LDL cholesterol and blood pressure compared with the Polycap. TIPS-2 also demonstrated that prescription of a full dose of Polycap leads to greater reduction in risk factors than prescription of a half dose, which may be theoretically expected to lead to an increased reduction of risk for ischemic heart disease and stroke of about 70% to 75%.

Trinomia/Sincronium has been tested in a multicenter, randomized, 2-group, parallel study (unpublished data). One hundred and seven patients with mild to moderate LDL- cholesterol elevation and normal blood pressure were randomized to receive either Trinomia or the three active components administered concomitantly. Follow-up was 8 weeks. Trinomia/Sincronium used as a single daily oral dose had similar efficacy in the reduction of LDL-cholesterol, VLDL-cholesterol, total cholesterol and triglyceride levels than the daily oral dose of the three reference drugs taken concomitantly. Changes from baseline to post-treatment were statistically significant, while there were no statistically significant differences between groups.

A pilot investigation was performed by the Pill Collaborative Group to determine the effect of a fixed dose combination pill called Red Heart Pill 1 (aspirin 75 mg, simvastatin 20 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg) formulated by Dr. Reddy’s Laboratories, Ltd.(23) The study assessed primary outcomes of total and LDL cholesterol and blood pressure after 12 weeks and found statistically significant reductions in patients prescribed the Red Heart Pill 1 compared with participants who received placebo. The study also assessed the adherence of patients to the study drug, 23% of patients on the Red Heart Pill 1 discontinued treatment. The study suggests an estimated 60% reduction of CHD and ischemic stroke risk through treatment with the Red Heart Pill in patients of similar risk.

Data for study populations, treatments and primary outcomes are summarized below in Table 2:

Table 2. Clinical trials evaluating fixed dose combination therapy for CVD prevention. Pill Collaborative TIPS TIPS II Group (2007-2008) (2012) (2011) Treatment Polycap Polycap/ Polycap Plus Red Heart Pill Population 2053 patients aged 518 patients aged 40 and older with 378 patients aged 18 45-80yrs with no previous vascular disease or and older with no previous CVD and diabetes mellitus indication and a 5-year one diagnosed risk estimated CVD risk factor over 7.5% Location India India Australia, Brazil, India, Netherlands, New Zealand, UK, & USA

8 Dosing for One capsule daily Two capsules Polycap plus 30 One daily Red Heart Pill treatment arm Polycap for 12 mEq/L potassium supplement daily for 12 weeks weeks for 8 weeks (n = 189) (n = 412) (n = 257)

Dosing for Comparative One capsule Polycap daily for 8 One daily placebo for treatment group combination or weeks 12 weeks singular drug (n = 261) (n = 189) therapy for 12 weeks (n = 1641) Follow-up 16 weeks from 8 weeks from randomization 16 weeks from randomization randomization Outcomes Referent All groups with no Low dose Polycap Placebo equivalent drug for target marker LDL cholesterol -27.1 mg/dL -6.6 mg/dL* -0.8 mmol/L (24.0, 30.2) p=0.006 p<0.0001 Total 32.1 mg/dL -7.2 mg/dL* -0.8 mmol/L cholesterol p<0.0001 p=0.014 p<0.001

Blood pressure -7.4/5.6 mmHg* -2.8/1.7 mmHg* -9.9/5.3 mm Hg (SBP/DBP) p<0.0001 p=0.003, p=0.001 p<0.0001, p<0.001

Heart rate -7.0 bpm No difference - p<0.0001

Discontinuation/ 16.0 % Polycap, 7.8% Polycap Plus, 23% RHP, Tolerability 14.8% Overall 6.9% Polycap, 18% Placebo *The effects of the full dose Polycap are incremental to that of the low dose Polycap.

Fixed dose combination therapy in patients with CVD A November 2012 report of the Red Heart Pill in secondary CVD prevention in the Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE) clinical trial presented at the American Heart Association Annual Scientific Sessions in Los Angeles demonstrated that this fixed dose combination is associated with a 33% increased adherence at 15 months compared with usual care.(15) The trial compared the effects of fixed dose combination-based care to usual care in 2,004 patients, half from India and half from Western Europe (UK, Ireland, Netherlands). Patients taking the Red Heart Pill also demonstrated lower systolic blood pressure (2.6 mmHg [95%CI 1.1, 4.0]) and low-density lipoprotein (LDL) cholesterol (4.2 mg/dl [1.9, 6.5]). These benefits were observed even though the usual care groups had treatment rates much higher than in the general population. Furthermore, separately significant benefits were observed in the participants from India and in participants from Western Europe.

9 Table 3. UMPIRE clinical trial primary outcomes. Fixed dose combination Usual Care Treatment Effect Outcome (n=1002) (n=1002) (95% CI) Adherence (%) 86% 65% 1.33 (1.26, 1.41) Systolic blood pressure, mmHg (SD) 129.2 (0.5) 131.7 (0.5) -2.6 (-4.0, -1.1) LDL cholesterol, mg/dl 82.8 (0.02) 87.0 (0.02) -4.2 (-6.5, -1.9)

Separate investigation is currently ongoing through FOCUS (Fixed Dose Combination Drug for Secondary cardiovascular Prevention) to examine the efficacy of Trinomia/Sincronium pill amongst patients in Europe, Argentina, Brazil and Paraguay.(24) The overall study aims is a proof of concept for Trinomia/Sincronium as a means for secondary CVD prevention with adherence as the primary outcome. Results are expected in early 2013.

11. Safety, Tolerance, and Monitoring Patient exposure to fixed dose combination formulations have been shown through clinical studies TIPS-1, TIPS-2, the Spanish pharmacodynamics study, and the Red Heart Pill study. The primary aims of these studies are proof of concept that the combinatorial effect of the fixed dose combination is not inferior to that of the individual agents and may offer improved adherence.

Safety Adverse Effects: Tables 4-8 demonstrate adverse events reported for TIPS-1, TIPS-2, Trinomia/Sincronium pill, Pill Collaborative, and Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial of Red Heart Pill. . Table 4. Incidence of adverse events among TIPS-1 patients. Treatment Group Side Effects P As T T+R T+At R+At T+R+At T+R+At+As S (n = 412) (n=205) (n=205) (n=209) (n=207) (n=205) (n=204) (n=204) (n=202) Dizziness or hypotension 6.3% 4.9% 3.9% 1.9% 2.9% 5.4% 5.4% 5.4% 2.5% Cough 5.3% 1.5% 3.4% 7.2% 0.5% 3.9% 3.9% 5.9% 1.0% Gastritis/dyspepsia 1.2% 2.0% 2.0% 3.3% 1.0% 2.9% 2.5% 1.0% 2.5% Fatigue 1.7% 1.0% 2.0% 1.4% 1.9% 2.0% 3.4% 0.5% 2.0% Bradycardia 0.2% 0% 0% 0% 1.0% 0% 0.5% 0.5% 0% Creatinine increase by >50% 8.5% 9.3% 6.8% 7.7% 9.7% 7.3% 7.4% 10.3% 7.9% Potassium >5.5 mmol/L 4.4% 5.9% 4.4% 5.3% 4.8% 5.9% 7.4% 6.9% 3.5% SGPT Doubled 2.9% 4.4% 3.4% 6.7% 4.8% 2.9% 0.5% 2.9% 5.0% A = Aspirin, T = Thiazide, R = Ramipril, At = Atenolol, S = Simvastatin, P = Polycap

Table 5. Incidence of adverse events among TIPS-2 patients. Treatment Group Side Effects Temporary or Permanent Discontinuation Permanent Discontinuation Low Dose Full Dose Polypill Low Dose Polypill Full Dose Polypill (n=261) (n=257) (n=261) (n=257) Number Discontinued 31 (11.9%) 36 (14.0%) 18 (6.9%) 20 (7.8%) Cough 3.4% 1.9% 1.9% 1.2% Dizziness 2.3% 2.3% 1.5% 1.2% Gastritis/ Dyspepsia 0.4% 3.5% 0.4% 2.7% Increased K+/Cr 0.4% 0.8% 0.4% 0.8% Surgery 0.4% 0.4% 0% 0% Other 5.4% 5.8% 2.7% 1.9%

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Table 6. Incidence of adverse events with Trinomia/Sincronium. Treatment Group Trinomia/Sincronium Three drugs separately Side Effects (n=53) (n=54) Adverse events, N 18 36 Patients with >1 AE, N (%) 13 (24.5%) 22 (40.7%) Patients with >1 IMP-related AE, N (%) 5 (9.4%) 7 (13%) Severe AE, N (%) 0 (0%) 0 (0%)

Table 7. Incidence of adverse events among Pill Collaborative patients (Red Heart Pill). Level of Severity and Treatment Group Patients Discontinuing Treatment Patients Remaining on Treatment Side Effects Polypill (n=44) Placebo (n=33) Polypill (n=145) Placebo (n=156) Gastric Irritation 3% 1% 12% 3% Increased bleeding tendency 0% 0% 2% 1% Cough 2% 1% 10% 2% Light Headed/ dizziness/ hypotension 4% 1% 15% 4% Muscle Pain or Weakness 1% 1% 7% 7% Headache 0% 0% 2% 2% Diarrhea 0% 0% 2% 3% Fatigue 2% 1% 7% 5% Abdominal Pain 0% 0% 2% 1% Constipation 0% 0% 5% 2% Flatulence 0% 0% 3% 3% Other 6% 6% 21% 15% Total 18% 13% 43% 31%

Table 8. Incidence of serious adverse events among UMPIRE patients (Red Heart Pill). Treatment Group Side Effects FDC (n=1002) Usual Care (n=1002) Cardiac disorders 11.8% 10.2% Infections & infestations 4.2% 2.7% Neoplasms, benign & malignant 1.3% 1.1% Vascular disorders 1.1% 1.2% Nervous system disorders 0.9% 1.3% Gastrointestinal disorders 1.0% 1.1% Other 3.6% 4% Total 15.4% 14.2%

Monitoring/Precautions: Monitoring and precautions of fixed dose combination therapy are similar to the individual components already included in the WHO’s Model List of Essential Medicines.

Contraindications: Contraindications of fixed dose combination therapy are similar to the individual components already included in the WHO’s Model List of Essential Medicines.

Professional Society Recommendations: The WHO has recommended fixed dose combination therapy for secondary CVD prevention. It has targeted fixed dose combination therapy as a “best buy” in the treatment and control of non-communicable, chronic diseases. The WHO’s recent announcement of voluntary targets for Member States includes the goal of treating at least 50% of patients with CVD with medications.

11 The 2012 European Society of Cardiology Guidelines on Cardiovascular Disease Prevention in Clinical Practice states that, “reducing dosage demands is the most effective single approach toward enhancing adherence.”(19) Fixed dose combination therapy is one such strategy to reduce dosage demands.

12. Summary of Available Data on Cost and Cost-Effectiveness Costs These costs represent the costs of individual drugs taken separately from the Supplier and Consumer perspectives. a) Supplier costs (all costs in USD).(25)

Median Cost Cost Equivalent Drug Strength/Qty per Tablet (USD) Qty in Polypill (USD) Aspirin 100 mg $0.0020 100 mg $0.0020 Simvastatin 20 mg $0.0595 20 mg $0.0595 Ramipril 5 mg $0.0150 5 mg $0.0150 (versus enalapril) Atenolol 50 mg $0.0102 50 mg $0.0102 Hydrochlorothiazide 50 mg $0.0053 12.5 mg $0.001325

Total supplier cost (components) = USD $0.088/tablet = USD $1.32/15 tablets. b) Consumer costs (costs in both USD$ and INR).

Drug Strength/Qty Cost per Tablet (USD) Cost per Tablet (INR) Aspirin 100 mg $0.014 0.725 Simvastatin 20 mg $0.271 14.05 Ramipril 5 mg $0.120 6.20 Atenolol 50 mg $0.008 0.40 Hydrochlorothiazide 12.5 mg $0.021 1.10

Total cost (components) = USD $0.43/tablet equivalent = USD $4.30 per 10 tablets. Total cost (components) = INR 22.5/tablet equivalent = INR 337.2 per 15 tablets.

For comparison, the costs for fixed dose combination therapy for CVD secondary prevention include: Indian Polycap (Cadila) Manufacturer’s Retail Price (retail cost): USD $4.45/INR 230.55 for 15 capsules. Trade Price (wholesale cost): USD $3.63/INR 188.49 for 15 capsules.(26)

Data from CIMS India suggest a similar cost of USD $2.72/INR 141.01 per 10 pill blister pack.(27)

Trinomia/Sincronium (Ferrer) In Latin America: Trinomia® Laboratory Sale Price (LSP) is €14-17/month (USD $18 - $22/month or $9-$11/15 tablets), which represents 30-50% of the LSP of 3 generics acquired separately (€25-50/month or $32-$65/month).(28)

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Cost Effectiveness A 2007 analysis by Lim and colleagues evaluated the use of a fixed dose combination therapy for individuals at high risk for CVD in 23 LMICs. These authors estimated that use of fixed dose combination therapy would lead to the prevention of 17.9 million deaths from cardiovascular disease (95% uncertainty interval 7.4 million – 25.7 million) over 10 years with more than half (56%) occurring in individuals less than 70 years. The cost would be US$4.7 billion per year ($3.3 billion – $6.1 billion) or $1.08 ($0.75 – $1.40) per person per year, ranging from $0.43 to $0.90 in low-income countries and from $0.54 to $2.93 in middle-income countries.(8) Cost effectiveness analyses by Gaziano et al. have estimated incremental cost effectiveness ratios (ICERs) for secondary CVD prevention of fixed dose combination therapy ranging from $306 per quality adjusted life year (QALY) to $388 per QALY gained.(29)

13. Summary of Regulatory Status Fixed dose combination therapy has been approved for use in India (Polycap) and Guatemala and México (Trinomia/Sincronium; soon to be available in Argentina and Nicaragua). The Indian Polycap and Trinomia/Sincronium are under current and forthcoming (January 2013) review by the United States Food and Drug Administration (FDA). Regulatory submissions for the Red Heart Pill are currently planned.

14. Availability of Pharmacopoeial Standards International Pharmacopoeia: Not available.

15. Proposed (new/adapted) text for the WHO Model Formulary We recommend that fixed dose combination therapy be added to the WHO Model Formulary for CVD secondary prevention. For the Formulary, we suggest, “Fixed dose combination therapy is useful for the treatment of stable ischemic heart disease and stroke secondary prevention.”

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